The clinical use of antibiotics in the 20th century has substantially decreased morbidity from bacterial infections. The early success of penicillin was extended by various sulfonamide drugs developed in the 1930s, and subsequently by a “golden” period of discovery, between 1945 and 1970, during which a wide array of highly effective agents are discovered and developed (Chopra, I., et al., “The Search for Antimicrobial Agents Effective against Bacteria Resistant to Multiple Antibiotics” Antimicrobial Agents and Chemotherapy, 1997, 41:497-503).
However, since the 1980s the introduction of new antibiotics has slowed, and, concurrently, there has been an alarming increase in bacterial resistance to existing agents that now constitutes a serious threat to public health (Brown, A. G. “Discovery and Development of New β-Lactam Antibiotics” Pure & Appl. Chem., 1987, 59:475-484). Hospitals, nursing homes and infant day care centers have become breeding grounds for the most tenacious drug-resistant pathogens (“Frontiers in Biotechnology” Science, 1994, 264:359-393). There has been an alarming rise in drug resistant staphylococci, enterococci, streptococci, and pneumococci infections, and a rise in tuberculosis, influenza and sepsis.
For several decades, β-lactam antibiotics have been widely used to control bacterial infections. Since the discovery of penicillin, countless numbers of analogues have been prepared and tested (see for example: U.S. Pat. No. 5,142,039 (Blaszczak et al.) and U.S. Pat. No. 5,338,861 (Botts et al.)), and a variety of successful modifications have been made to the five-membered ring, including (1) replacement of the sulfur atom with carbon or oxygen, (2) oxidation of the sulfur to the sulfoxide or sulfone, (3) enlargement to a larger ring, (4) incorporation of unsaturation, (5) attachment of additional fused rings, and (6) removal of the five-membered ring. As a result, new β-lactam ring systems have been introduced, including the penems, cephalosporins, carbapenems, oxapenems, oxacephams, as well as monocyclic, spirocyclic, and multicyclic β-lactams. In the case of monocyclic β-lactams (Sykes, R. B. et al. “Monocyclic β-Lactam Antibiotics Produced by Bacteria” Nature, 1981, 291:489-490), which directly relates to the present invention, removal of the five-membered ring leaves a four-membered β-lactam ring, the structural core of which is 2-azetidinone (1): 
Monocyclic antibiotics successfully developed by derivatization of this core structure include the monobactams (Slusarchyk, W. A. et al. “Monobactams: Ring Activating N-1-Substituents in Monocyclic β-Lactam Antibiotics” Heterocycles, 1984, 21:191-209), which have 2-oxoazetidine sulfonic acid as their characteristic structure. A key feature of the monobactams is the activation of the β-lactam ring towards nucleophilic attack by bacterial transpeptidases that is caused by the electron-withdrawing potential of the sulfonated nitrogen atom. Alternative activating groups for monobactam derivatives have been discovered, including phosphate, phosphonate, and analogues in which a spacer atom is interposed between the ring nitrogen and activating group (Breuer, H. et al. “[(2-oxo-1-azetidinyl)oxy]acetic acids: a new class of synthetic monobactams” J. Antibiotics, 1985, 38:813-818; Slusarchyk, W. A. et al. “Monobactams: Ring Activating N-1-Substituents in Monocyclic β-Lactam Antibiotics” Heterocycles, 1984, 21:191-209).
The primary targets of β-lactams are the penicillin binding proteins, a group of bacterial proteins that mediate the final step of bacterial cell wall biosynthesis in which a terminal alanine-alanine linkage of a peptidoglycan strand is cleaved by an active site serine and cross-linked to another peptidoglycan fragment, thus strengthening the bacterial cell wall. Penicillin interrupts this cross-linking step by acylating the serine with its reactive β-lactam ring. Following acylation, ring opening results in further chemical fragmentations that are deleterious to the enzyme. Also among the penicillin binding proteins are the β-lactamases; enzymes that degrade β-lactams. Clavulinic acid targets these enzymes, and is therefore useful in conjunction with established penicillins in combination therapies for combating certain resistant strains of bacteria (Chopra, I. et al. “The Search for Antimicrobial Agents Effective against Bacteria Resistant to Multiple Antibiotics” Antimicrobial Agents and Chemotherapy, 1997, 41:497-503).
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming extremely difficult to treat with conventional antibiotics, leading to a sharp rise in clinical complications (Binder, S. et al. Science, 1999, 284:1311). For additional articles and discussions on antimicrobial drug resistance: http://www.cdc.gov/ncidod/dbmd/antibioticresistance. The need for new antibiotics and protocols for treating MRSA infections is extremely serious.
There is a clear need for new antibacterial agents to combat pathogenic bacteria that have become resistant to current antibiotics. Towards this end, a novel class of derivatized, N-thiolated, monocyclic β-lactams have been developed in the present invention, that exhibit strong antibacterial activity against a wide variety of species and strains, including methicillin-resistant Staphylococcus aureus. 